Genes 2 Brains 2 Mind 2 Me

While most presentations at SfN cover brief snippets of research, yesterday it was a delight to hear the story of neurexins and neuroligins – the whole, decades worth of research, story – from Professor Thomas Sudhof, whose lab has been responsible for the purification and biochemical characterization of these proteins.  Without re-telling the tale here, a few neat highlights about these proteins who form a transynaptic bridge with neurexins on the pre-synaptic membrane binding to neuroligins on the post-synaptic membrane:
-neurexins were first purified using alpha-latrotoxin (a.k.a black widow venom!)

-there are thousands of spice variants of a single neurexin gene and these have rather specific affinities for different splice variants of neuroligins (how are these splicing events regulated to ensure the right pairs find each other?)

-the mere act of ectopic expression of neuroligins is sufficient induce the formation of synapses in neuronal cell lines – however this will not happen if the neuroligin is missing its neurexin binding domain.  Apparently, different neuroligin genes confer the formation of different types of inhibitory vs. excitatory synapses.

-interestingly, the deletion of any pair of the 3 (NL1,2,3) neuroligin genes has little effect – albeit for a few subtle social behavior phenotypes in mice.  Deletion of all 3 of the NL genes is lethal.

-In humans, mutations in neuroligins such as R87W and R451C are associated with autism spectrum disorder.  Apparently, these mutations do not fold properly and do not make it to the cell surface.

-The R451C mutation, when expressed in a mouse leads to more inhibitory synapses in the cortex and more excitatory synapses in the hippocampus.  The mice are BETTER able to learn/unlearn the water-maze paradigm but show subtle social affiliation phenotypes.

-There are a number of other mutations in genes that interact with the neurexins and neuroligins that are also associated with mental disability, suggesting that the proper regulation of synaptic organization and excitatory/inhibitory balance is a key aspect of optimal mental function.